The mammalian genome contains ˜28 million CpG sites, about 60% of which are methylated at the 5 position of the cytosine (Rollins et al., 2006). Methylation of relatively CpG-rich promoters causes very strong transcriptional repression (Stein et al., 1982, Lorincz et al., 2002); promoter methylation is largely restricted to imprinted genes, transposon promoters, and to CpG islands on the inactive X chromosome. Many experiments have demonstrated faithful inheritance of methylation patterns over many cell divisions in somatic cells (Wigler et al., 1981; Lorincz et al., 2002) and over many sexual generations in plants, which contain a DNA methylating system similar to that of vertebrates (reviewed by Goll and Bestor, 2005). This heritability means that genomic methylation patterns could have many biological functions, and many such functions have been proposed. The most familiar of these is gene control during development (Holliday and Pugh, 1975; Riggs, 1975). Other proposed functions include genome stability (Chen at al., 1996) learning and memory (Miller and Sweatt, 2007; this claim is highly controversial), defense against transposons (Yoder at al., 1997; Bestor, 2003), and X chromosome inactivation (Panning and Jaenisch, 1996). While much controversy remains, the ability of promoter methylation to silence transcription and the heritability of genomic methylation patterns are supported by a large and compelling body of evidence.
Null mutations in any of the three DNA methyltransferases are recessive lethals, and loss of DNMT3L causes male sterility and maternal effect lethality in females. Mutations in the DNA methyltransferase gene DNMT3B cause ICE syndrome, which is characterized by a combined immunodeficiency usually fatal in childhood, very unstable centromeres of chromosomes 1, 9, and 16, and mild but characteristic facial anomalies (Xu at al., 1999). Partial demethylation or hypermethylation in mutant mice lead to abnormal expression of imprinted genes with early lethality (Biniszkiewicz 2002; Yamada at al., 2005). While the normal function of the mammalian genome clearly depends on genomic methylation patterns, the abnormalities of genomic methylation patterns found in human disease have been difficult to discern because of the lack of methods for the methylation profiling of the entire genome.